tbuckley/cabot-search huggingface dataset:
Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, <i>BRAF<sup>V600E</sup></i> metastatic and/or unresectable colorectal cancer: SWOG S2107.
Authors: Van K. Morris, Katherine A Guthrie, Scott Kopetz, Rimini Breakstone, Thomas Benjamin Karasic, Zishuo Ian Hu, Shay Bellasea, Marwan Fakih, Sepideh Gholami, Philip Jordan Gold, Philip Agop Philip
Journal: Journal of Clinical Oncology (2023)

TPS265 Background: Patients with microsatellite stable (MSS), BRAF V600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with a reported overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAF V600E mCRC. In preclinical models of MSS, BRAF V600E CRC, inhibition of BRAF and EGFR induces a loss of expression of mismatch repair genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAF V600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAF V600E mCRC. Methods: In this prospective phase II clinical trial (N = 75), patients with previously treated MSS, BRAF V600E mCRC will be randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients will receive E (300 mg PO daily) and C (500 mg/m 2 IV every 14 days), and patients in the experimental arm will receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α = .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months and a hazard ratio of 0.57. Additional patient specimens will be collected for exploratory correlative research. The study activated across the United States in June 2022 and as of September 2022 has enrolled 2 of 75 planned participants. Funding: NIH/National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by The Hope Foundation for Cancer Research STrS award. Clinical trial information: NCT05308446 .
Demographic and regional trends of gastrointestinal (GI) cancer mortality in adolescents and young adults (AYA) in the US, 1999-2019.
Authors: S. M. Qasim Hussaini, Amanda L. Blackford, Ramy Sedhom, Arjun Gupta
Journal: Journal of Clinical Oncology (2023)

786 Background: There is an alarming rise in incidence of GI cancers in AYAs that face unique social challenges in navigating their healthcare and receiving guideline-concordant care. There is limited data on mortality trends in this understudied group. We investigated age-adjusted mortality rates (AAMRs) in young adults with GI cancer. Methods: We utilized the CDC WONDER database to analyze deaths among young adults aged 15 to 44 years from GI cancer (ICD 15-26) from 1999 to 2019. We calculated AAMRs per 100,000 and stratified by sex, race/ethnicity, census, and urban metro (population &gt;1,00,000), medium/small (50,000 – 999,999) or rural area (&lt;50,000) per NCHS Classification Scheme. We used Joinpoint regression software (v4.9) to establish annual percentage change (APC) trends. Results: Between 1999 and 2019, there were 73,954 deaths from GI cancer in young adults (39% female, 16% Hispanic, 20% non-Hispanic Black, 16% rural, 42% Southern-located, 52% colorectal, and 17% each pancreatic, hepatobiliary, and gastric cancers). Overall AAMR over study period was 3.3. Among subgroups, the AAMR was higher in men (3.9), non-Hispanic Black adults (4.6), and rural areas (3.7). Time analysis by year showed overall stability or slight decrease in AAMRs between 1999-2009, followed by an increase from 2009-2019. This was especially notable in Hispanic individuals. Earlier increases in AAMR were noted in rural (since 2004) and Midwestern (since 2001) locations. Highest AAMRs were noted in Southern states (Mississippi, Kentucky, West Virginia, and Alabama). Compared to our younger cohort, older adults (45+) had expectedly higher but recorded significantly better AAMR improvements during study period. Conclusions: Mortality rates for AYAs with GI cancers remained relatively stable from 1999 to 2009, but have since risen, with significant sociodemographic and regional variation. These data highlight the need to better understand risk factors (diet, environmental, and other), screening trends, and variation in receipt of guideline-concordant care to ensure appropriate and equitable risk reduction and cancer management in AYAs.[Table: see text]
Endoscopic management of gastrointestinal wall defects, fistula closure, and stent fixation using through-the-scope tack and suture system
Authors: Arunkumar Krishnan, Sardar M. Shah-Khan, Yousaf Hadi, Neel Patel, Shyam Thakkar, Shailendra Singh
Journal: Endoscopy (2023)

BACKGROUND : Multiple devices are available for tissue approximation. A new through-the-scope suturing (TTSS) device has recently been introduced; however, data on its scope of use and clinical effectiveness are limited. We aimed to assess the clinical course and effectiveness of this TTSS device. METHODS : A retrospective review was performed for consecutive patients who underwent TTSS application. Primary outcomes were technical and clinical success, and secondary outcomes included adverse events and long-term clinical success. RESULTS : 53 patients (mean age 67.8 years; 69.8 % females) were included, with a mean defect size of 32.6 mm (SD 11.9). Technical success was achieved in 51 patients (96.2 %). Clinical success was achieved in 49 patients (92.4 %). Two patients (3.8 %) experienced failed fistula closure after technical success. Long-term follow-up (> 30 days) was available for 45 patients (84.9 %), with a mean follow-up of 7.2 months. One patient (1.9 %) had self-reported bleeding that did not require further intervention. CONCLUSIONS : TTTS was an effective and safe method for the closure of large gastrointestinal defects and could be used for fistula closure and stent fixation, making it a valuable addition to the armamentarium of endoscopic closure devices.
Perioperative changes in geriatric functions of elderly patients undergoing surgical resection for gastric cancer.
Authors: Chie Tanaka, Mitsuro Kanda, Koki Nakanishi, Shinichi Umeda, Dai Shimizu, Yoshikuni Inokawa, Hideki Takami, Masamichi Hayashi, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera, Norifumi Hattori
Journal: Journal of Clinical Oncology (2023)

811 Background: Little knowledge is available for postsurgical changes in cognitive and physical functions that may be useful for considering indication for surgery in elderly patients with gastric cancer. We therefore conducted a prospective study aimed to determine the influence of gastrectomy on these patients. Methods: We recruited patients older than 75 years for whom gastrectomy for gastric cancer had been planned, and assessed their cognitive and physical functions, daily activities, episodes of depression, confusion, and delirium before surgery (baseline), upon discharge, and at 6 months after surgery (POM 6). Results: Among 54 elderly patients registered between February 2017 and February 2020. There were no significant decreases in MMSE scores between baseline and at POM 6, nor were there significant differences in physical function and indicators of depression and confusion between these time points. As many as 20% of patients were found to have the functional decline on the basic activities of daily living scores (BADL) after surgery compared with the baseline. The only variable significantly associated with a functional decline in BADL was postoperative complications. Conclusions: Postoperative cognitive functions did not significantly decline when compared with the baseline scores, although postoperative BADL scores of patients who experienced postoperative complications were significantly lower than those who did not.
Outcomes of patients with hepatocellular carcinoma (HCC) treated in the lenvatinib (LEN) and immunotherapy era (2018-2021) compared to the sorafenib (SOR) era (2008-2018).
Authors: Chloe Lim, Carla Pires Amaro, Philip Q. Ding, Winson Y. Cheung, Vincent C. Tam
Journal: Journal of Clinical Oncology (2023)

553 Background: SOR was the standard first-line treatment for HCC for about a decade until the approval of LEN. Subsequently, atezolizumab + bevacizumab (A+B) were shown to have superior efficacy outcomes. The aim of this study was to compare effectiveness outcomes of HCC patients treated in the SOR era compared to the post-SOR era, when most HCC patients received first-line LEN or A+B. Methods: All HCC patients who started first-line systemic therapy at cancer centres in the Canadian province of Alberta between January 1, 2008 and December 31, 2021 were included in this study. Overall survival (OS), progression-free survival (PFS), and clinician-assessed response rate (RR) were retrospectively analyzed. Since LEN was first available to patients in Canada in August 2018, patients who started first-line systemic therapy between January 2008 to July 2018 were classified as treated in the “SOR era”, while patients treated from August 2018 to December 2021 were classified as being treated in the “post-SOR era”. Results: Of 372 total patients included, 230 were treated in the SOR era and 142 in the post-SOR era. Demographic and clinical characteristics are as follows for the SOR era and post-SOR era groups, respectively: median age was 63 and 64 years, 80% and 81% were male, 24% and 11% were of East Asian ethnicity. Most patients were ECOG 0-1 (85% and 91%), Child-Pugh A (84% and 85%), and ALBI grade 1 or 2 (96% and 98%) prior starting first-line therapy. Most common causes of liver disease included excess alcohol use (24% and 30%), Hepatitis C (37% and 48%), and Hepatitis B (27% and 15%). Most patients had advanced (BCLC C) stage disease in both groups (91% and 87%). Prior to systemic treatment 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT respectively. See table for first-line treatments received and outcomes. Median treatment duration was 3.2 months and 4.8 months, and median follow-up time was 9.6 and 11.0 months for SOR era and post-SOR era, respectively. Conclusions: In this real-world multicenter retrospective study, patients treated in the post-SOR era, where LEN and A+B were the more common first-line treatments, had superior overall survival, first-line response rates and progression-free survival. This study confirms the real-world progress that has been made in improving outcomes of HCC patients through systemic treatment advancements over the last 15 years.[Table: see text]
Osteoarthritis in people over 16: diagnosis and management—updated summary of NICE guidance
Authors: George Wood, Julie Neilson, Elizabeth Cottrell, Stephen P Hoole
Journal: BMJ (2023)

### What you need to know Osteoarthritis is a common condition that causes joint pain and stiffness and often has a negative impact on a person's quality of life. More than 8.5 million people have osteoarthritis in the UK.1 Multisite peripheral joint pain is common, with the knee, hip, hand, and foot joint sites being most commonly affected.2 This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE) guideline for the diagnosis and management of osteoarthritis.3 The recommendations cover all joint sites apart from spinal osteoarthritis. The update emphasises the importance of core treatments of therapeutic exercise and weight management in the management of osteoarthritis, alongside information and support and the use of pharmacological management only if needed to support non-pharmacological treatments. NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Committee's (GC) experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. Definitions of evidence certainty are given in box 1. Box 1 ### GRADE Working Group grades of evidenceRETURN TO TEXT
Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations
Authors: Junyi Xin, Mulong Du, Dongying Gu, Kewei Jiang, Mengyun Wang, Mingjuan Jin, Yeting Hu, Shuai Ben, Silu Chen, Wei Shao, Shuwei Li, Haiyan Chu, Linjun Zhu, Chen Li, Kun Chen, Kefeng Ding, Zhengdong Zhang, Hongbing Shen, Meilin Wang
Journal: Genome Medicine (2023)

The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10-8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.
Use of high-dimensional and spatial immune profiling to explore sotigalimab (CD40 agonist) activation of antigen presenting cells and T cells in the tumor microenvironment in patients with esophageal/gastroesophageal junction cancer.
Authors: Maira Soto, Erin L Filbert, Hai Yang, Li Zhang, Stephanie Starzinski, Alec Starzinski, Alexander Cheung, Tony Li, Frank J. Hsu, Andrew H. Ko, Lawrence Fong, Bridget P Keenan
Journal: Journal of Clinical Oncology (2023)

450 Background: Neoadjuvant chemoradiation (CRT) followed by surgical resection is standard of care for patients with locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer. A pathologic complete response (pCR) at surgery is associated with improved survival outcomes. Sotigalimab (sotiga) is a potent CD40 agonist mAb capable of inducing and expanding anti-tumor immune responses. A recently reported non-randomized phase II clinical trial of sotiga combined with CRT in E/GEJ cancer patients showed promising pCR rates that compared favorably to historical data 1 . Here, deep immune profiling was performed on a subset of patients to gain insight into the mechanism of sotiga. Methods: In the initial safety cohort (n=6) of this phase II E/GEJ clinical trial, tumor and blood samples were obtained pre-treatment and again following a single lead-in dose of sotiga, prior to initiation of CRT. Immune modulation in the tumor microenvironment and blood of patients was examined using high dimensional techniques, including mass cytometry, multiplexed ion beam imaging, and single cell RNA sequencing. Results: Sotiga administration dramatically re-models the tumor microenvironment, inducing immune infiltration and shifting the immune composition predominantly toward an inflammatory phenotype. At baseline, E/GEJ tumors were infiltrated with myeloid cells and T cells, the majority of which were T regs . Sotiga increased antigen-presenting cell (APC) infiltration in tumors and activated dendritic cells as demonstrated by expression of MHCII and CD86. Sotiga treatment also induced infiltration of activated cytotoxic T cells and decreased the proportion of T regs . There was also evidence of T cell activation in peripheral blood with increased expression of 4-1BB, CTLA-4, ICOS and PD-L1. Therapeutic responses to sotiga were associated with distinct T cell signatures both at baseline and on-treatment. At baseline, pCR patients (representing 4 of the 6 pts (67%) in this cohort) had a higher ratio of memory CD4 + T cells to T regs which further increased following sotiga treatment, whereas patients who did not have a pCR had a higher proportion of myeloid cells at baseline and did not show a decrease in T reg cells after sotiga treatment. Conclusions: Sotiga induced dramatic changes in the tumor microenvironment including increased frequency of activated T cells and APCs, and decreased frequency of T regs . A distinct signature of T cell infiltration in baseline tumor biopsies was observed in patients who achieved a pCR versus those who did not, potentially identifying patients that may benefit from this novel treatment strategy.
Serum IL-6 level to predict survival and treatment response in gastric and gastroesophageal junction cancer.
Authors: John D Karalis, Michelle R Ju, Lynn Y Yoon, Esther C Castro-Dubon, Suntrea Hammer, Matthew R. Porembka, Sam C. Wang
Journal: Journal of Clinical Oncology (2023)

444 Background: There are few biomarkers to guide treatment for gastric and gastroesophageal junction adenocarcinoma (G+GEJ). The systemic inflammatory response, which is reflected by circulating serum cytokine levels, of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. Methods: A retrospective review of a prospectively maintained biobank was performed to identify patients diagnosed with G+GEJ from 2016-2022. Pre-treatment serum was collected at the time of diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately prior to surgical resection. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. In patients who received neoadjuvant therapy, we assessed whether the change in IL-6 (ΔIL-6) after therapy was associated with TRG. Results: We first measured the pre-treatment levels of 17 different cytokines in a 67-patient cohort to determine if certain circulating cytokines were prognostic for OS. In a multivariable analysis adjusted for clinical stage and the expression level of the other cytokines, the only circulating cytokine level that was independently associated with OS was IL-6 (HR: 1.06 per 1 pg/ml increase, 95% CI: 1.04-1.08). We then analyzed the serum IL-6 level in an additional 134 patients, resulting in a final cohort of 201 patients. Serum IL-6 level ranged from 0.3-196.7 pg/ml. In a multivariable analysis adjusted for age, sex, clinical stage, pathologic differentiation, Lauren classification, H. pylori status and neutrophil-to-lymphocyte ratio, IL-6 level was independently associated with OS (HR: 1.012 per 1 pg/ml increase, 95% CI: 1.006-1.019). Patients in the top tercile of pre-treatment IL-6 level had worse median OS (10.6 months) compared to patients in the intermediate (17.4 months) and bottom tercile (35.8 months, p &lt; 0.0001). Among patients who received neoadjuvant therapy (n = 50), ΔIL-6 ≤ 0 had a sensitivity of 80% and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 1). Conclusions: Pre-treatment serum level of IL-6 is a promising prognostic biomarker for patients with G+GEJ. ΔIL-6 may predict response to neoadjuvant therapy.
The SHARON trial: A study of melphalan, BCNU, hydroxocobalamin, ascorbic acid, and autologous stem cell rescue for metastatic pancreatic cancer with an inherited BRCA mutation.
Authors: Kenneth H. Yu, Colin D. Weekes, Yi-Bin Albert Chen, Jeffrey Aaron Glazier, Arnold Glazier, Parastoo Dahi, Sergio Giralt, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2023)

TPS774 Background: SHARON is a phase 1, single-arm trial to assess the safety and preliminary efficacy of 2 cycles of melphalan, BCNU, hydroxocobalamin (vitamin B12b), dose-escalated vitamin C, and autologous stem cells in patients with stage IV pancreatic cancer and an inherited, deleterious BRCA1/2 mutation. Cancers that evolve in patients with a germline BRCA1/ 2 mutation generally have loss or inactivation of the wild type allele, which results in hypersensitivity to melphalan. The melphalan dose-response is log-linear: doubling the melphalan area under the curve (AUC) doubles the log reduction in clonogenic survival. The melphalan AUC that can safely be achieved with melphalan followed by stem cell rescue has the potential to provide major log reductions in cancer cell survival in BRCA-deficient cancers. However, reversion mutations in BRCA can cause resistance to DNA-crosslinking agents such as melphalan. Studies have shown that oxidizing cellular glutathione (GSH) to glutathione disulfide (GSSG) can inhibit DNA repair and hypersensitize wild-type cancer cells to melphalan. In this trial, BCNU, vitamin B12b, and vitamin C are used to increase cancer cell GSSG levels. Methods: Eligibility criteria include stage IV pancreatic cancer, an inherited deleterious BRCA1/2 mutation, life expectancy of at least 6 months, measurable or non-measurable disease, and suitability for apheresis, chemotherapy, and stem cell infusion. Prior treatment with PARP inhibitors is allowed. Stem cells are collected by apheresis. Participants receive 2 cycles of melphalan 100 mg/m 2 , BCNU 150 mg/m 2 , vitamin B12b 1.45 g/m 2 , and vitamin C 3, 6, or 8 g/m 2 on Day −2. Stem cell infusion administered on day 0. A 2 + 4 dose-escalation schedule is employed for vitamin C. Adverse reactions summarized by CTCAE 5.0. The primary endpoint is safety, and secondary endpoints are objective response rate (overall and for metastatic lesions) and overall and progression-free survival. Amendment pending to include stage IV, BRCA-related, HER2-negative breast cancer and PALB2 mutations. The trial is enrolling at Memorial Sloan Kettering Cancer Center and Massachusetts General Hospital. Clinical trial information: NCT04150042 .